Doxorubicin is an effective and widely used chemotherapeutic to treat leukaemia and solid cancers including breast cancer. However, the drug also causes severe side-effects such as cardiomyopathy and intestinal mucositis. The precise molecular mechanisms by which doxorubicin mediates its anticancer effects and the pathological side-effects remain poorly defined. We found that doxorubicin-mediated activation of the innate immune receptor ZBP1 greatly contributed to its immunopathological intestinal side-effects. Now, we wish to explore this fundamental finding further and identify the molecular mechanisms by which doxorubicin induces ZBP1 activation. We will study the role of ZBP1 in mouse models of doxorubicin-induced intestinal mucositis and cardiomyopathy. Finally, we will investigate whether ZBP1 signalling contributes to the establishment of anticancer immune responses following doxorubicin treatment. Together, this work will lead to a better understanding of how chemotherapeutic drugs interact with the immune system and may on the longer term inspire new strategies to treat the severe side-effects of doxorubicin, for example by inhibiting ZBP1 activation.